Access to pyridyl-substituted 1,3,5-triazines from 4 H-pyrido[1,3]oxazin-4- ones via a cyclocondensation process

Article abstract of DOI:10.1021/jo5010668

Pyridyl-substituted 1,3,5-triazines were synthesized in good to excellent yields via an unprecedented one-step cyclocondensation of 4H-pyrido[1,3]oxazin- 4-ones with amidines at room temperature or under microwave irradiations. The broad applicability was demonstrated by 33 examples with a variety of amidines and three different 4H-pyrido[1,3]oxazin-4-one chemical series. In addition, a one-pot process from 4H-pyrido[1,3]oxazin-4-one precursors (imide sodium salts) was developed and led to the desired triazines compounds, thus allowing a one-step economy in their global synthetic preparation. This approach provides rapid access to pyridyl (or pyridone)-substituted 1,3,5-triazines with high potential in various fields of application.

Full text of DOI:10.1021/jo5010668

Article
pubs.acs.org/joc
Access to Pyridyl-Substituted 1,3,5-Triazines from
4H‑Pyrido[1,3]oxazin-4-ones via a Cyclocondensation Process
Laetitia Le Falher,‡,§ Omar Ben Ayad,† Ozge Ziyaret,† Alexander Mamontov,‡,§ Candice Botuha,*,‡,§
Serge Thorimbert,*,‡,§ and Franck Slowinski*,†
†Exploratory Unit, Sanofi R&D, 1 Avenue Pierre Brossolette, 91385 Chilly Mazarin Cedex, France
‡Sorbonne Universites
́
, UPMC Universite
́
Paris 6, UMR 8232, Institut Parisien de Chimie Molec
́
ulaire, F-75005 Paris, France
§
CNRS, UMR 8232, Institut Parisien de Chimie Molec
́
ulaire, F-75005 Paris, France
S
* Supporting Information
ABSTRACT: Pyridyl-substituted 1,3,5-triazines were synthesized in good to excellent yields via an unprecedented one-step
cyclocondensation of 4H-pyrido[1,3]oxazin-4-ones with amidines at room temperature or under microwave irradiations. The
broad applicability was demonstrated by 33 examples with a variety of amidines and three different 4H-pyrido[1,3]oxazin-4-one
chemical series. In addition, a one-pot process from 4H-pyrido[1,3]oxazin-4-one precursors (imide sodium salts) was developed
and led to the desired triazines compounds, thus allowing a one-step economy in their global synthetic preparation. This
approach provides rapid access to pyridyl (or pyridone)-substituted 1,3,5-triazines with high potential in various fields of
application.
INTRODUCTION
■
In the past decades, 2,4,6-substituted 1,3,5-triazines have
emerged as central building blocks for the elaboration of
supramolecular structures,1 dendrimers,2 and ligands for
transition-metal complexes.3 Such chemical entities have
found applications in many fields of materials science such as
electroluminescence devices, liquid crystals, and organic light-
emitting diodes (OLEDs), among others.4 Besides, 2,4,6-
substituted 1,3,5-triazine-based bioactive compounds have been
also developed.5
Other interesting examples are the 2-(2′-hydroxyphenyl)-
1,3,5-triazines reported as UV absorbers and possessing a
crucial 2-hydroxyphenyl substituent.6 Moreover, pyridyl-sub-
stituted 1,3,5-triazines have been reported as precursors of
conducting or semiconducting polymers,4a,7 ligands for
transition-metal complexes exhibiting photophysical proper-
ties,8 and promising medicinal compounds (e.g., adenosin
receptor antagonists, protein kinases, and mTOR inhibitors)
(Figure 1).9
Figure 1. Selected examples of 2,4,6-substituted 1,3,5-triazines and
their applications.
There are well-established methods to form 2,4,6-substituted
1,3,5-triazines exhibiting two identical substituents. Cyclo-
trimerizations and cycloadditions with nitriles have been used
extensively to prepare simple aryl-substituted triazines, but the
yields remain low.4a,d,7,8a,b,10 On the other hand, 2,4,6-
substituted 1,3,5-triazines exhibiting three different substituents
are often prepared by the sequential incorporation of each
substituent onto cyanuric chloride.2a,b,9b,c,11
Received: May 15, 2014
© XXXX American Chemical Society
A
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Figure 2. Accesses to pyridyl-substituted 1,2,4-oxadiazoles, 1,2,4-triazoles, and 1,3,5-triazines.
Scheme 1. Transformations of Pyrido-oxazinones 1a, 2a, and 3a into Triazines 5a, 6a, and 7a, Respectively
a
b
c
d
Isolated yields using reaction conditions (a)/(b)/(c). Total conversion after 30 min. Not determined. Obtained as its pyridone tautomer (solid
state).
We wish here to report a complementary, alternative,
microwave (MW)-assisted] in the presence of 1.05 equiv of
benzamidine (4a), applying a modified version of a procedure
described for similar transformations of benzo-oxazinones6a−e
(Scheme 1).
efficient, and short access to 2,4,6-substituted 1,3,5-triazines
bearing a pyridyl substituent. We recently disclosed an
expeditive route to various 2-substituted 4H-pyrido[1,3]-
oxazin-4-ones via an intramolecular O-arylation (Figure 2).12
We were able to derivatize these compounds into pyridyl-
substituted 1,2,4-triazoles and 1,2,4-oxadiazoles in one step,
applying the procedures described for similar transformations
of 4H-benzo[e][1,3]oxazin-4-ones.13 Similarly, we envisioned
the one-step conversion of these 2-substituted 4H-pyrido[1,3]-
oxazin-4-ones into pyridyl-substituted 1,3,5-triazines. To the
best of our knowledge, such a transformation to produce 2,4,6-
substituted 1,3,5-triazines exhibiting a pyridyl substituent has
not been reported to date. Our objective was also to reduce the
number of synthetic steps to get to these structures by
developing their direct preparation (two steps in one pot) from
the 2-substituted 4H-pyrido[1,3]oxazin-4-one precursors (the
imide sodium salts) (Figure 2)
Herein we disclose our study to determine the optimal
reaction conditions for the cyclocondensation process and the
extension of this methodology to a wide panel of 2-substituted
4H-pyrido[1,3]oxazin-4-ones12 and amidines. Finally, a one-pot
procedure from N-oxo-substituted bromo(iso)nicotinamides
(pyrido-oxazinone precursors) is also described, thus providing
a one-step economy in the global preparation of these
compounds.
First, at room temperature, in the presence of 4a in ethanol,
the reaction proceeded in good to excellent yields, leading to
the corresponding products (4,6-diphenyl-1,3,5-triazin-2-yl)-
pyridinols 5a (66%) and 6a (81%) and 3-(4,6-diphenyl-1,3,5-
triazin-2-yl)pyridin-2(1H)-one (7a) (91%). Under these
conditions, we observed a faster conversion of 3a (only 30
min) compared with the conversions of 1a and 2a (12 h). In
refluxing ethanol, the same reaction furnished 5a after 12 h in
an improved yield of 91%, while 6a was isolated in only 67%
yield. Finally, 1a, 2a, and 3a were submitted to microwave
irradiation at 130 °C for 10 min, and 5a, 6a, and 7a were
obtained in good to excellent yields (91, 90, and 77%,
respectively) with fewer byproducts in the reaction mixture.
Because of its efficiency, the short time needed, and the
excellent purity of the resulting compounds, this microwave-
assisted protocol was chosen for further exemplification.
To further extend the synthetic scope of this reaction, we
investigated the reactivity of several pyrido-oxazinones bearing
an aryl or heteroaryl substituent (R) at C-2 (1a−d, 2a−g, and
3a−e) with six different amidine derivatives: 4a (R′ = Ph), 4-
fluorobenzamidine hydrochloride (4b) (R′ = 4-F-Ph),
morpholinoformamidine hydrobromide (4c) (R′ = morpho-
linyl), guanidine hydrochloride (4d) (R′ = NH2), S-
methylisothiourea hemisulfate (4e) (R′ = SMe), and acetamide
hydrochloride (4f) (R′ = Me) (Scheme 2). These amidines
were chosen on the basis of their possible application for the
synthesis of biologically active 1,3,5-triazines.
RESULTS AND DISCUSSION
■
With pyrido-oxazinones 1a, 2a, and 3a as models, the
transformation into triazines was realized using three different
sets of reaction conditions [room temperature, reflux, or
B
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Scheme 2. Synthesis of Triazines 5a−i, 6a−l, and 7a−i from Pyrido-oxazinones 1a−d, 2a−g, and 3a−e under MW-Assisted
Reaction Conditions
a
b
1a, R = Ph; 1b, R = 4-F-Ph; 1c, R = N-Me-pyrrole; 1d, R = 4-MeO-Ph. 2a, R = Ph; 2b, R = 4-F-Ph; 2c, R = N-Me-pyrrole; 2d, R = 4-MeO-Ph; 2e,
c
R = 3-MeO-Ph; 2f, R = 4-Cl-Ph; 2g, R = 2-naphthyl. 3a, R = Ph; 3b, R = 4-MeO-Ph; 3c, R = 4-F-Ph; 3d, R = N-Me-pyrrole; 3e, R = 2-thiophenyl.
d
4a = benzamidine (R′ = Ph); 4b = 4-fluorobenzamidine hydrochloride (R′ = 4-F-Ph); 4c = morpholinoformamidine hydrobromide (R′ =
e
morpholinyl); 4d = guanidine hydrochloride (R′ = NH2). Reaction was run using 1 to 1.05 equiv of K2CO3.
In the presence of 4a, this synthetic process occurred in good
to excellent yields (from 55% for 6j up to 91% for 5a) with a
wide compatibility regarding the substituent at the C-2 position
over the three pyrido-oxazinone chemical series explored.
Monosubstituted aryls exhibiting an electron-withdrawing
group (5b, 6b, 6i, 7c) or an electron-donating one (5d, 6d,
7b) were well-tolerated, as were a meta-substituted aryl group
(6g), a naphthyl group (6j), and heteroaryl substituents such as
N-methylpyrrole (5c, 6c, 7d) and thiophene (7e).
potassium carbonate was added to the reaction mixture to
generate the corresponding free bases and to allow the
cyclocondensation to proceed (see Table S1 in the Supporting
Information). Interestingly, the reaction of 4b with the pyrido-
oxazinones 1a, 2a, and 3a (R = Ph) led to 5b (74%), 6b (87%),
and 7c (73%) respectively. These triazines were previously
isolated from the cyclocondensation of 4a (R′ = Ph) with
pyrido-oxazinones 1b, 2b, and 3c (R = 4-F-Ph) in 68, 75, and
72% yield, respectively. In both cases, these triazines were
obtained in good and similar yields independent of the amidine
used. In addition, the cyclocondensations of 4b with pyrido-
oxazinones 1b and 2b (R = 4-F-Ph) provided the
Other amidine derivatives were also employed, such as 4b−d.
These were obtained from commercial sources as hydro-
chloride or hydrobromide salts. Consequently, 1 equiv of
C
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Table 1. One-Pot Process for the Preparation of Triazines 5, 6, and 7 from Imide Sodium Salts 8, 9, and 10
entry
SM
R
R′
product
one-pot yield (%)
sequential yield (%)
a
1
2
8a
Ph
Ph
Ph
5a
5d
5i
71
62
63
68
34
73
60
51
48
71
58
49
a
8d
4-MeO-Ph
4-MeO-Ph
4-F-Ph
75
b
3
8d
morpholinyl
74
a
4
8b
Ph
5b
6a
6h
6i
47
a
5
9a
Ph
Ph
45
b
6
9d
4-MeO-Ph
4-Cl-Ph
Ph
morpholinyl
56
a
7
9f
Ph
48
d
c
e
f
8
10a
10b
10c
10c
Ph
7a
84 /58
d
c
9
4-MeO-Ph
4-F-Ph
Ph
7b
75 /71
d
c
10
11
Ph
7c
48
d
b
4-F-Ph
morpholinyl
7h
55
a
b
c
Reaction was run in DMSO at 180 °C for 30 min. Reaction was run in DMSO at 180 °C for 30 min with 1 equiv of K2CO3. Reaction was run in
d
e
f
MeCN at 150 °C for 30 min. Obtained as its pyridone tautomer. Multigram scale: Yield obtained using 2 g of 10a. Multigram scale: Yield
obtained using 2 g of 10b.
corresponding 4-(4,6-bis(4-fluorophenyl)-1,3,5-triazin-2-yl)-
pyridinols 5e and 6e in good yields (63−78%). These could
be considered as hydroxylated analogues of the conductive
polymer precursor depicted in Figure 1,4a (synthesized in two
steps in 21% overall yield). The yields were improved with
pyrido-oxazinones exhibiting a p-methoxyphenyl substituent at
C-2 (1d and 3b), which furnished 5f and 7f in 80−91% yield.
Finally, exposure to guanidine partners 4c and 4d gave
morpholino-1,3,5-triazine (5g−i, 6f, 6h, 7h, 7i) and amino-
1,3,5-triazine derivatives (6k, 6l, 7g) in good to excellent yields
(61 up to 97%). This represents one of the most expeditive
accesses to these structures, which may find useful applications
in the field of medicinal chemistry.9
Unfortunately, when the above-mentioned procedure was
used, the reaction of pyrido-oxazinone 2a with 4e (R′ = SMe)
did not provide the corresponding triazine. A complex mixture
of unidentified compounds was obtained in this case. The use
of 4f (R′ = Me) with 1a and 2a led to the corresponding
triazines in only moderate yields (51−57%) and unsatisfactory
purity (see Table S1 in the Supporting Information).
Although this synthetic process appears to be efficient, rapid,
and compatible with a wide panel of substituents, pyridyl cores,
and amidine partners, we were interested in developing a more
expeditive protocol. From the optimal reaction conditions
developed for the synthesis of the above-mentioned pyrido-
oxazinones [MW-assisted intramolecular O-arylation of N-
(hetero)aroyl(iso)nicotinamide sodium salts]12 and for the
preparation of these pyridyl-substituted 1,3,5-triazines (MW,
EtOH, 130 °C, 10 min), a one-pot procedure should be
attainable: Starting from a mixture of the imide sodium salt 8, 9,
or 10 (easily obtained in one step by benzoylation of
commercial chloro- or bromonicotinamides) and the amidine
partner (with 1 equiv of potassium carbonate if needed), the
microwave-assisted one-pot experiment should be performed at
180 °C in DMSO or 150 °C in MeCN for 30 min (see Scheme
S1 in Supporting Information). These are the adequate and
unique conditions for the intramolecular O-arylation (the first
of the two steps of the one-pot process) to proceed. Thereby,
microwave irradiation of an equimolar mixture of imide 8a and
benzamidine 4a in DMSO furnished the desired 1,3,5-triazine
5a in 71% yield (Table 1, entry 1). Although a purification step
was necessary to eliminate several polluting byproducts, the
yield of this one-pot process was better than the overall yield of
the two sequential steps (8a to 1a = 68%12 and 1a to 5a = 91%;
overall yield = 62%).
Similarly, the one-pot transformation of 8b and 8d into 5b,
5d, and 5i (Table 1, entries 2−4) occurred in better yields than
in the sequential two-step chemical pathway (75% vs 63%; 74%
vs 68%; and 47% vs 34%). Except for one example (Table 1,
entry 10), the same trend was observed for the preparation of
triazines 7a, 7b, and 7h (Table 1, entries 8, 9 and 11). The best
result was obtained with imide salt 10a (chlorine atom at the C-
2 position of the pyridine). The yield of the transformation of
10a into 7a was significantly improved via the one-pot process
(84% vs 48% for the sequential pathway). This could be
explained by the higher yield of the O-arylation step12
(compared with the two above-mentioned chemical series)
and by the less drastic reaction conditions (MeCN, 150 °C),
reducing the degradation and undesired side reactions. In
addition, the use of acetonitrile as the solvent allowed an easier
workup (no aqueous workup). Moreover, on a multigram scale,
7a and 7b were isolated in significant yields of 58 and 71%,
respectively, using 2 g of 10a and 10b (Table 1, entries 8 and
9).
Except for 6a, the same one-pot transformation of precursors
containing a 3,5-dibromo-pyridine motif (Table 1, entries 6 and
7) led to the corresponding triazines 6h and 6i in similar yields
compared with their two-step synthesis.
On the basis of the aforementioned results, we propose a
plausible reaction mechanism for the one-pot transformation.
The imide sodium salt first undergoes the intramolecular O-
arylation process to give the corresponding pyrido-oxazinone
D
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Scheme 3. Proposed Mechanism for the One-Pot Process
purchased at a purity of >99.9%. Reactions involving air- or moisture-
sensitive reagents or intermediates were carried out under an inert
atmosphere of nitrogen or argon in glassware that had been oven-dried
and then nitrogen-purged. Reaction temperatures are reported as the
temperature of the bath surrounding the vessel, unless otherwise
indicated. Flash chromatography was conducted according to the
established Still protocol16 using appropriately sized disposable
(I). Next, nucleophilic attack on nonisolated (I) by the
corresponding amidine furnishes N-acylamidine intermediate
(II), which gives the desired triazine after the cyclo-
condensation/dehydration sequence (Scheme 3).
Finally, starting from commercial halogenonicotinamides,
these triazines were synthesized in two steps: (1) formation of
the imide salt (with an average yield around 90%) followed by
(2) a one-pot O-arylation/cyclocondensation process with
yields of 45−84%. To our knowledge, this constitutes the most
rapid and efficient access to trisubstituted 1,3,5-triazines
possessing a pyridyl (or pyridone) substituent reported to date.
The hydroxy group on the pyridine of the 1,3,5-triazines
prepared herein (5 and 6) may be useful for physical
applications as a result of the intramolecular H-bond with
one nitrogen atom of the triazine core.14 Besides, valuable
chemical transformations of this hydroxy group are currently
under investigation. On the other hand, the resulting pyridone
in compounds 7 may be of great interest for medicinal
purposes.15
1
columns of normal-phase silica with the indicated solvents. H and
13C (or J-MOD) NMR spectra were taken in deuterated chloroform
(CDCl3) or deuterated dimethyl sulfoxide (DMSO-d6), unless
otherwise noted. Chemical shifts (δ) are expressed in parts per
1
million referenced to the residual solvent (i.e., H 7.24 ppm, 13C 77.1
ppm for chloroform; 1H 2.50 ppm, 13C 39.5 ppm for dimethyl
sulfoxide). Splitting patterns are expressed as follows: s, singlet; d,
doublet; t, triplet; q, quartet; p, pentet; m, multiplet; comp,
overlapping multiplets of magnetically nonequivalent protons; br,
broad; app, apparent. IR spectra were recorded on films or in solution
with the indicated solvent. Microwave-assisted reactions were
performed using a Biotage Initiator 2.0 apparatus in Biotage 2−5 or
10−20 mL microwave vials at the indicated temperature (detected by
an IR sensor) in very high absorption mode for the indicated period of
time. The spectral data and detailed procedures for the preparation of
the following compounds have been already reported: 1a−d, 2a−e, 2g,
3a, 3c, 3d, 8a, 8b, 8d, 9a, and 9d.12
CONCLUSION
■
We have developed a rapid and efficient access to pyridyl-
containing trisubstituted 1,3,5-triazines. Starting from previ-
ously described pyrido-oxazinones, we were able to generate
the corresponding triazines in one step under microwave-
assisted reaction conditions in good to excellent yields. This
process was successfully applied to a wide panel of pyrido-
oxazinones exhibiting aryl or heteroaryl substituents at C-2 and
different types of pyridine cores in the presence of various
amidine derivatives. Moreover, a one-pot process starting from
the pyrido-oxazinone precursors (imide salts) allowed the
access to these final compounds to be shortened. Importantly,
this work provides a rapid and efficient way to prepare pyridyl-
1,3,5-triazines with wide chemical diversity, leading to
compounds of high interest in various fields of application.
General Procedure A: 4-(4,6-Diphenyl-1,3,5-triazin-2-yl)-
pyridin-3-ol (5a). At room temperature under an argon atmosphere,
to a solution of commercial benzamidine (4a) (56 mg, 0.47 mmol) in
ethanol (10 mL) was added 2-phenyl-4H-pyrido[4,3-e][1,3]oxazin-4-
one (1a) (100 mg, 0.45 mmol), and the resulting mixture was stirred
at room temperature under argon for 12 h. Then the mixture was
concentrated in vacuo, and the resulting residue was purified by flash
chromatography eluting with CH2Cl2/AcOEt 100/0 to 50/50 to
provide 96 mg (66% yield) of the desired product as a white solid. 1H
NMR (500 MHz, CDCl3) δ 12.60 (br s, 1H), 8.65 (d, J = 7.2 Hz, 4H),
8.54 (s, 1H), 8.48 (d, J = 5.1 Hz, 1H), 8.35 (d, J = 5.1 Hz, 1H), 7.78 (t,
J = 7.3 Hz, 2H), 7.71 (t, J = 7.7 Hz, 4H); 13C NMR (125 MHz,
DMSO-d6) δ 170.5 (2C), 170.4, 155.3, 141.6, 140.5, 134.3 (2C), 133.8
(2C), 129.3 (4C), 128.8 (4C), 123.4, 0.121.6; IR (film, cm−1) 3427,
3061, 1590, 1570, 1536, 1513, 1506, 1486, 1449, 1406, 1387, 1361,
1302, 1241, 1217, 1187, 1147, 1135, 1093, 1067, 1057, 1050, 1027,
1002, 927, 906, 870, 846, 825, 812, 784, 743, 690, 679, 650, 641, 611,
573, 549, 474; MS ESI+ m/z 327.1238 [C20H15N4O (M + 1) requires
327.1240]; mp 250−251 °C.
EXPERIMENTAL SECTION
■
General Information. Unless otherwise indicated, all starting
materials, reagents, and catalysts were obtained from commercial
suppliers and used without further purification. Anhydrous tetrahy-
drofuran (THF), methanol (MeOH), ethanol (EtOH), dichloro-
methane (CH2Cl2), ethyl acetate (AcOEt), cyclohexane (Cy), and
diethyl ether (Et2O) were purchased with quality standards for
analysis. Acetonitrile (MeCN) was purchased with quality standards
for HPLC. Prior to use, THF was subsequently dried over activated
molecular sieves (4 Å). Anhydrous dimethyl sulfoxide (DMSO) was
General Procedure B: 4-(4,6-Diphenyl-1,3,5-triazin-2-yl)-
pyridin-3-ol (5a). Under an argon atmosphere, to a solution of
commercial 4a (54 mg, 0.45 mmol) in ethanol (10 mL) was added 1a
(100 mg, 0.45 mmol). The resulting mixture was refluxed for 12 h.
Then the reaction mixture was cooled to room temperature and
concentrated in vacuo, and the resulting residue was purified by flash
chromatography eluting with CH2Cl2/ethyl acetate 100/0, 90/10, 80/
E
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20, 70/30, 60/40, 50/50 to provide 132 mg (91% yield) of the desired
compound as a white solid.
MS ESI+ m/z 345.1145 [C20H14FN4O (M + 1) requires 345.1146];
mp 257−259 °C.
General Procedure C: 4-(4,6-Diphenyl-1,3,5-triazin-2-yl)-
pyridin-3-ol (5a). In a 10−20 mL microwave vial, to a solution of
commercial 4a (54 mg, 0.45 mmol) in ethanol (10 mL) was added 1a
(100 mg, 0.45 mmol). Then the microwave vial was sealed and
submitted to microwave irradiation for 10 min at 130 °C using a
Biotage Initiator 2.0 apparatus (in very high absorption mode). After
10 min, the vial was opened, and the reaction mixture was
concentrated in vacuo. The resulting residue was then purified by
flash chromatography eluting with CH2Cl2/ethyl acetate 100/0, 90/10,
80/20, 70/30, 60/40, 50/50 to provide 133 mg (91% yield) of the
desired compound as a white solid.
4-(4-(1-Methyl-1H-pyrrol-2-yl)-6-phenyl-1,3,5-triazin-2-yl)pyridin-
3-ol (5c). The title compound was obtained in 84% yield (0.101 g) as a
yellow powder from 2-(1-methyl-1H-pyrrol-2-yl)-4H-pyrido[4,3-e]-
[1,3]oxazin-4-one (1c) (83 mg) according to general procedure C. 1H
NMR (400 MHz, DMSO-d6) δ 12.86 (br s, 1H), 8.48 (dt, J = 8.6, 3.2
Hz, 2H), 8.47 (s, 1H), 8.33 (d, J = 5.1 Hz, 1H), 8.29 (d, J = 5.1 Hz,
1H), 7.73 (tt, J = 7.2, 1.2 Hz, 1H), 7.66 (tt, J = 7.7, 1.6 Hz, 2H), 7.44
(dd, J = 4.1, 1.8 Hz, 1H), 7.35 (t, J = 2.1 Hz, 1H), 6.32 (dd, J = 4.1, 2.4
Hz, 1H), 4.23 (s, 3H); J-MOD 13C NMR (100 MHz, DMSO-d6) δ
169.5, 169.4, 164.4, 155.4, 141.4, 140.4, 134.5, 133.6, 133.4, 129.2
(2C), 128.5 (2C), 127.6, 123.2, 121.2, 119.6, 109.5, 38.6; IR (film,
cm−1) 3427, 3028, 2954, 1617, 1589, 1574, 1538, 1512, 1488, 1477,
1467, 1438, 1401, 1366, 1353, 1306, 1272, 1242, 1242, 1217, 1168,
1146, 1134, 1093, 1068, 1055, 1027, 1013, 991, 909, 870, 844, 824,
801, 788, 761, 735, 710, 691, 677, 663, 658, 647, 641, 616, 604, 570,
549; MS ESI+ m/z 330.1347 [C19H16N5O (M + 1) requires
330.1349]; mp 209−211 °C.
5-Bromo-4-(4,6-diphenyl-1,3,5-triazin-2-yl)pyridin-3-ol (6a). The
title compound was obtained in 81% yield (0.108 g) as a yellow
powder from 5-bromo-2-phenyl-4H-pyrido[4,3-e][1,3]oxazin-4-one
(2a) (100 mg) according to general procedure A, 67% yield (61
mg) from 2a (68 mg) according to general procedure B, and 90% yield
1
(120 mg) from 2a (100 mg) according to general procedure C. H
NMR (500 MHz, DMSO-d6) δ 10.80 (br s, 1H), 8.62 (dt, J = 7.1, 1.5
Hz, 4H), 8.41 (s, 1H), 8.39 (s, 1H), 7.73 (tt, J = 7.3, 1.3 Hz, 2H), 7.65
(tt, J = 7.8, 1.6 Hz, 4H); J-MOD 13C NMR (125 MHz, DMSO-d6) δ
171.5, 171.3 (2C), 151.8, 141.6, 138.0, 134.6 (2C), 133.5 (2C), 132.4,
129.1 (4C), 128.7 (4C), 118.4; IR (film, cm−1) 3432, 3069, 2747,
1599, 1588, 1544, 1504, 1466, 1446, 1395, 1349, 1330, 1314, 1303,
1196, 1179, 1156, 1134, 1067, 1053, 1028, 1006, 929, 895, 845, 814,
741, 699, 687, 678, 660, 648, 611, 565; MS ESI+ m/z 405.0346
[C20H14BrN4O (M + 1) requires 405.0346]; mp 218−220 °C.
3-(4,6-Diphenyl-1,3,5-triazin-2-yl)pyridin-2(1H)-one (7a). The
title compound was obtained in 91% yield (0.133 g) as a white
powder from 2-phenyl-4H-pyrido[3,2-e][1,3]oxazin-4-one (3a) (100
mg) according to general procedure A (in 30 min) and 77% yield (112
4-(4-(4-Methoxyphenyl)-6-phenyl-1,3,5-triazin-2-yl)pyridin-3-ol
(5d). The title compound was obtained in 83% yield (0.116 g) as a
white powder from 2-(4-methoxyphenyl)-4H-pyrido[4,3-e][1,3]-
1
oxazin-4-one (1d) (100 mg) according to general procedure C. H
NMR (400 MHz, CDCl3) δ 12.89 (s, 1H), 8.58 (d, J = 8.6 Hz, 2H),
8.57 (s, 1H), 8.55 (d, J = 2.6 Hz, 2H), 8.41 (d, J = 5.2 Hz, 1H), 8.30
(d, J = 5.2 Hz, 1H), 7.62 (tt, J = 7.1, 1.2 Hz, 1H), 7.56 (t, J = 7.9 Hz,
2H), 7.04 (dt, J = 8.9, 2.7 Hz, 2H), 3.91 (s, 3H); J-MOD 13C NMR
(100 MHz, CDCl3) δ 170.8, 170.6, 170.5, 164.2, 156.2, 142.1, 140.3,
134.8, 133.4, 131.1 (2C), 129.0 (2C), 128.9 (2C), 126.9, 123.4, 121.4,
114.4 (2C), 55.5; IR (film, cm−1) 3432, 3012, 2932, 2839, 2040, 1913,
1607, 1587, 1570, 1533, 1507, 1488, 1448, 1423, 1408, 1390, 1362,
1341, 1305, 1262, 1219, 1175, 1145, 1134, 1114, 1067, 1058, 1050,
1025, 1002, 995, 914, 853, 840, 822, 788, 766, 732, 694, 675, 663, 651,
643, 634, 616, 611, 594, 572, 551, 512; MS ESI+ m/z 357.1342
[C21H17N4O2 (M + 1) requires 357.1346]; mp 182−184 °C.
4-(4,6-Bis(4-fluorophenyl)-1,3,5-triazin-2-yl)pyridin-3-ol (5e). The
title compound was obtained in 63% yield (0.094 g) as a pale-yellow
powder from 1b (100 mg) in the presence of 4b (76 mg, 0.43 mmol)
and potassium carbonate (60 mg, 0.43 mmol) according to general
procedure D. 1H NMR (400 MHz, CDCl3) δ 12.62 (s, 1H), 8.59 (ddt,
J = 8.9, 5.4, 2.1 Hz, 4H), 8.53 (br s, 1H), 8.39 (d, J = 5.1 Hz, 1H), 8.28
(d, J = 5.0 Hz, 1H), 7.22 (tt, J = 8.6, 2.1 Hz, 4H); J-MOD 13C NMR
(100 MHz, CDCl3) δ 171.0, 170.2 (2C), 166.5 (d, J = 254 Hz, 2C),
156.2, 142.3, 140.5, 131.6 (d, J = 9.3 Hz, 4C), 130.7 (d, J = 3.0 Hz,
2C), 123.1, 121.4, 116.3 (d, J = 21.9 Hz, 4C); 19F NMR (188 MHz,
CDCl3) δ −104.3; IR (film, cm−1) 3432, 3066, 2925, 1601, 1572,
1533, 1508, 1489, 1415, 1387, 1363, 1304, 1237, 1220, 1188, 1157,
1144, 1104, 1051, 1012, 860, 840, 817, 798, 768, 654, 636, 609, 591,
586, 571, 550, 508; MS ESI+ m/z 363.1061 [C20H13F2N4O (M + 1)
requires 363.1052]; mp 302−303 °C.
1
mg) from 2a (100 mg) according to general procedure C. H NMR
(500 MHz, DMSO-d6) δ 12.19 (br s, 1H), 8.66 (d, J = 7.4 Hz, 4H),
8.57 (br d, J = 5.8 Hz, 1H), 7.78 (br s, 1H), 7.70 (t, J = 7.2 Hz, 2H),
7.64 (t, J = 7.6 Hz, 4H), 6.50 (br s, 1H); 13C NMR (100 MHz,
DMSO-d6) δ 171.5, 170.6 (2C), 160.2, 144.2, 141.3, 135.4 (2C), 132.9
(2C), 128.9 (4C), 128.6 (4C), 124.9, 105.4; IR (film, cm−1) 3432,
3066, 1665, 1605, 1589, 1557, 1535, 1515, 1482, 1450, 1416, 1367,
1345, 1310, 1255, 1224, 1179, 1148, 1067, 1026, 1001, 888, 844, 813,
775, 755, 696, 681, 652, 643, 636, 601; MS ESI+ m/z 327.1241
[C20H15N4O (M + 1) requires 327.1240]; mp 249−251 °C.
4-(4-(4-Fluorophenyl)-6-phenyl-1,3,5-triazin-2-yl)pyridin-3-ol
(5b). The title compound was obtained in 68% yield (0.096 g) as a
white powder from 2-(4-fluorophenyl)-4H-pyrido[4,3-e][1,3]oxazin-4-
one (1b) (100 mg) according to general procedure C or using general
procedure D described below.
General Procedure D: 4-(4-(4-Fluorophenyl)-6-phenyl-1,3,5-
triazin-2-yl)pyridin-3-ol (5b). In a 10−20 mL microwave vial, to a
solution of commercial 4-fluorobenzamidine hydrochloride (4b) (82
mg, 0.47 mmol) and potassium carbonate (65 mg, 0.47 mmol) in
ethanol (10 mL) was added 1a (100 mg, 0.45 mmol). Then the
microwave vial was sealed and submitted to microwave irradiation for
10 min at 130 °C using a Biotage Initiator 2.0 apparatus (in very high
absorption mode). After 10 min, the vial was opened, and the reaction
mixture was concentrated in vacuo. The resulting residue was then
purified by flash chromatography eluting with CH2Cl2/ethyl acetate
100/0, 90/10, 80/20, 70/30, 60/40, 50/50 to provide 114 mg (74%
yield) of the desired compound as a white solid. 1H NMR (400 MHz,
CDCl3) δ 12.66 (s, 1H), 8.59 (ddt, J = 8.9, 5.4, 2.1 Hz, 2H), 8.54 (d, J
= 7.2 Hz, 1H), 8.52 (d, J = 4.4 Hz, 2H), 8.37 (d, J = 5.1 Hz, 1H), 8.27
(d, J = 5.1 Hz, 1H), 7.61 (tt, J = 7.3, 1.3 Hz, 1H), 7.53 (tt, J = 7.7, 1.6
Hz, 2H), 7.20 (tt, J = 8.6, 1.5 Hz, 2H); J-MOD 13C NMR (100 MHz,
CDCl3) δ 171.1, 170.9, 170.3, 166.4 (d, J = 254 Hz, 1C), 156.2, 142.3,
140.5, 134.4, 133.7, 131.6 (d, J = 9.3 Hz, 2C), 130.8 (d, J = 2.9 Hz,
1C), 129.1 (4C), 123.1, 121.3, 116.2 (d, J = 21.8 Hz, 2C); 19F NMR
(188 MHz, CDCl3) δ −104.6; IR (film, cm−1) 3424, 3059, 2924, 2853,
1602, 1588, 1572, 1534, 1507, 1486, 1449, 1417, 1406, 1386, 1362,
1303, 1237, 1217, 1187, 1153, 1144, 1133, 1100, 1056, 1027, 1013,
1002, 855, 841, 822, 786, 765, 728, 693, 680, 591, 586, 571, 549, 504;
4-(4-(4-Fluorophenyl)-6-(4-methoxyphenyl)-1,3,5-triazin-2-yl)-
pyridin-3-ol (5f). The title compound was obtained in 91% yield
(0.134 g) as a white powder from 1d (100 mg) in the presence of 4b
(72 mg, 0.41 mmol) and potassium carbonate (57 mg, 0.41 mmol)
1
according to general procedure D. H NMR (400 MHz, CDCl3) δ
12.77 (s, 1H), 8.56 (ddt, J = 6.9, 5.4, 2.1 Hz, 2H), 8.48 (dt, J = 9.0, 2.0
Hz, 2H), 8.49 (s, 1H), 8.34 (d, J = 5.1 Hz, 1H), 8.25 (d, J = 5.1 Hz,
1H), 7.18 (tt, J = 8.9, 2.1 Hz, 2H), 7.00 (tt, J = 9.0, 2.1 Hz, 2H), 3.86
(s, 3H); J-MOD 13C NMR (100 MHz, CDCl3) δ 170.6, 170.4, 169.8,
166.3 (d, J = 254 Hz, 1C), 164.3, 156.2, 142.2, 140.4, 131.4 (d, J = 9.3
Hz, 2C), 131.1 (2C), 131.0 (d, J = 3.1 Hz, 1C), 126.7, 123.2, 121.3,
116.1 (d, J = 21.8 Hz, 2C), 114.4 (2C), 55.6; 19F NMR (188 MHz,
CDCl3) δ −105.0; IR (film, cm−1) 3432, 2938, 2841, 1601, 1585,
1571, 1535, 1506, 1464, 1417, 1388, 1363, 1308, 1261, 1235, 1219,
1174, 1145, 1114, 1100, 1057, 1029, 998, 859, 838, 815, 768, 653, 638,
610, 590, 571, 551, 513; MS ESI+ m/z 375.1259 [C21H16FN4O2 (M +
1) requires 375.1252]; mp 196−197 °C.
4-(4-Morpholino-6-phenyl-1,3,5-triazin-2-yl)pyridin-3-ol (5g).
The title compound was obtained in 70% yield (0.105 g) as a white
powder from 1a (100 mg) in the presence of morpholinoformamidine
F
dx.doi.org/10.1021/jo5010668 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
hydrobromide (4c) (98 mg, 0.47 mmol) and potassium carbonate (65
mg, 0.47 mmol) according to general procedure D. H NMR (400
1H), 8.48 (dt, J = 7.1, 1.5 Hz, 2H), 8.36 (s, 1H), 8.34 (s, 1H), 7.68 (tt,
J = 7.4, 1.3 Hz, 1H), 7.60 (tt, J = 7.2, 1.6 Hz, 2H), 7.40 (dd, J = 4.0, 1.8
Hz, 1H), 7.28 (t, J = 2.1 Hz, 1H), 6.26 (dd, J = 4.0, 2.5 Hz, 1H), 4.18
(s, 3H); J-MOD 13C NMR (100 MHz, DMSO-d6) δ 170.6, 170.4,
165.7, 152.0, 141.5, 138.0, 135.1, 133.1, 132.9, 132.7, 129.0 (2C),
128.5 (2C), 128.0, 119.3, 118.6, 109.1, 38.4; IR (film, cm−1) 3428,
3066, 2954, 2862, 1586, 1557, 1537, 1508, 1479, 1458, 1446, 1433,
1391, 1365, 1342, 1308, 1268, 1194, 1178, 1155, 1141, 1094, 1065,
1054, 1027, 1013, 1003, 995, 895, 861, 844, 819, 786, 760, 735, 708,
689, 681, 657, 650, 616, 603, 565, 506; MS ESI+ m/z 408.0453
[C19H15BrN5O (M + 1) requires 408.0454]; mp 167−169 °C.
5-Bromo-4-(4-(4-methoxyphenyl)-6-phenyl-1,3,5-triazin-2-yl)-
pyridin-3-ol (6d). The title compound was obtained in 81% yield
(0.106 g) as a yellow powder from 5-bromo-2-(4-methoxyphenyl)-4H-
pyrido[4,3-e][1,3]oxazin-4-one (2d) (100 mg) according to general
1
MHz, CDCl3) δ 13.33 (s, 1H), 8.49 (s, 1H), 8.34 (dt, J = 7.2, 1.4 Hz,
2H), 8.22 (d, J = 5.1 Hz, 1H), 8.16 (d, J = 5.1 Hz, 1H), 7.59 (tt, J =
7.3, 1.2 Hz, 1H), 7.51 (t, J = 7.7 Hz, 2H), 4.10 (t, J = 5.2 Hz, 2H), 4.02
(t, J = 4.6 Hz, 2H), 3.83 (t, J = 5.1 Hz, 4H); J-MOD 13C NMR (100
MHz, CDCl3) δ 170.2, 169.8, 163.6, 156.4, 142.0, 140.0, 134.9, 132.8,
128.8 (2C), 128.5 (2C), 123.6, 121.1, 66.7, 66.6, 44.0, 43.9; IR (film,
cm−1) 3430, 3070, 2977, 2922, 2866, 1594, 1565, 1502, 1488, 1454,
1440, 1412, 1370, 1352, 1308, 1265, 1251, 1221, 1174, 1142, 1116,
1069, 1051, 1024, 1002, 974, 929, 908, 870, 856, 823, 787, 766, 710,
692, 679, 670, 642, 617, 579, 552, 544; MS ESI+ m/z 336.1448
[C18H18N5O2 (M + 1) requires 336.1455]; mp 257−258 °C.
4-(4-(4-Fluorophenyl)-6-morpholino-1,3,5-triazin-2-yl)pyridin-3-
ol (5h). The title compound was obtained in 70% yield (0.102 g) as a
pale-yellow powder from 1b (100 mg) in the presence of 4c (91 mg,
0.43 mmol) and potassium carbonate (60 mg, 0.43 mmol) according
to general procedure D. 1H NMR (400 MHz, CDCl3) δ 13.18 (s, 1H),
8.48 (s, 1H), 8.37 (ddt, J = 9.0, 5.4, 2.2 Hz, 2H), 8.22 (d, J = 5.1 Hz,
1H), 8.16 (d, J = 5.1 Hz, 1H), 7.18 (tt, J = 8.6, 2.1 Hz, 2H), 4.08 (t, J =
4.4 Hz, 2H), 4.01 (t, J = 4.4 Hz, 2H), 3.83 (t, J = 5.1 Hz, 4H); J-MOD
13C NMR (100 MHz, CDCl3) δ 170.2, 168.8, 165.9 (d, J = 253 Hz,
1C), 163.5, 156.3, 142.0, 140.1, 131.1, 130.9 (d, J = 9.1 Hz, 2C), 123.5,
121.1, 115.9 (d, J = 21.7 Hz, 2C), 66.6, 66.5, 44.0, 43.9; 19F NMR (188
MHz, CDCl3) δ −106.1; IR (film, cm−1) 3430, 3043, 2974, 2924,
2876, 1603, 1575, 1561, 1497, 1489, 1454, 1441, 1422, 1403, 1372,
1304, 1272, 1264, 1250, 1227, 1174, 1156, 1142, 1114, 1103, 1072,
1057, 1002, 974, 930, 872, 858, 814, 771, 746, 702, 657, 636, 588, 577,
550, 542, 509; MS ESI+ m/z 354.1355 [C18H17FN5O2 (M + 1)
requires 354.1360]; mp 251−253 °C.
1
procedure C. H NMR (400 MHz, CDCl3) δ 12.99 (br s, 1H), 8.64
(d, J = 7.3 Hz, 2H), 8.63 (d, J = 7.1 Hz, 2H), 8.52 (s, 1H), 8.46 (s,
1H), 7.65 (tt, J = 7.2, 1.4 Hz, 1H), 7.58 (tt, J = 7.6, 1.6 Hz, 2H), 7.08
(dt, J = 9.0, 2.0 Hz, 2H), 3.93 (s, 3H); J-MOD 13C NMR (100 MHz,
CDCl3) δ 171.1, 171.0, 170.2, 164.7, 157.1, 145.4, 141.2, 135.1, 134.0,
131.9 (2C), 129.6 (2C), 129.4 (2C), 127.4, 123.8, 119.5, 114.9 (2C),
56.0; IR (film, cm−1) 3428, 3065, 2935, 2840, 1605, 1585, 1541, 1499,
1466, 1448, 1424, 1402, 1393, 1352, 1306, 1260, 1196, 1176, 1155,
1137, 1115, 1069, 1054, 1028, 1003, 894, 854, 834, 787, 765, 731, 693,
676, 659, 653, 635, 618, 595, 566, 522; MS ESI+ m/z 435.0459
[C21H16BrN4O2 (M + 1) requires 435.0451]; mp 168−170 °C.
4-(4,6-Bis(4-fluorophenyl)-1,3,5-triazin-2-yl)-5-bromopyridin-3-ol
(6e). The title compound was obtained in 78% yield (0.107 g) as a
yellow powder from 2b (100 mg) in the presence of 4b (57 mg, 0.33
mmol) and potassium carbonate (43 mg, 0.31 mmol) according to
general procedure D. 1H NMR (400 MHz, CDCl3) δ 12.58 (br s, 1H),
8.69 (ddt, J = 9.3, 5.4, 2.2 Hz, 4H), 8.55 (s, 1H), 8.49 (s, 1H), 7.29 (tt,
J = 8.8, 2.0 Hz, 4H); J-MOD 13C NMR (100 MHz, DMSO-d6) δ
172.0, 170.8 (2C), 165.9 (d, J = 251 Hz, 2C), 152.2, 142.0, 138.4,
132.7, 132.0 (d, J = 9.4 Hz, 4C), 131.5 (d, J = 2.2 Hz, 2C), 118.8,
116.6 (d, J = 21.9 Hz, 4C); 19F NMR (188 MHz, CDCl3) δ −105.8;
IR (film, cm−1) 3431, 3077, 1599, 1541, 1504, 1456, 1417, 1403, 1385,
1349, 1300, 1238, 1194, 1152, 1135, 1103, 1013, 897, 862, 853, 827,
770, 689, 587, 561, 523, 511; MS ESI+ m/z 441.0156
[C20H12BrF2N4O (M + 1) requires 441.0157]; mp 168−171 °C.
5-Bromo-4-(4-morpholino-6-phenyl-1,3,5-triazin-2-yl)pyridin-3-
ol (6f). The title compound was obtained in 70% yield (0.096 g) as a
yellow powder from 2a (100 mg) in the presence of 4c (73 mg, 0.35
mmol) and potassium carbonate (48 mg, 0.35 mmol) according to
4-(4-(4-Methoxyphenyl)-6-morpholino-1,3,5-triazin-2-yl)pyridin-
3-ol (5i). The title compound was obtained in 89% yield (0.128 g) as a
white powder from 1d (100 mg) in the presence of 4c (87 mg, 0.41
mmol) and potassium carbonate (57 mg, 0.41 mmol) according to
1
general procedure D. H NMR (400 MHz, CDCl3) δ 13.47 (s, 1H),
8.48 (s, 1H), 8.31 (dt, J = 9.0, 2.0 Hz, 2H), 8.21 (d, J = 5.1 Hz, 1H),
8.16 (d, J = 5.1 Hz, 1H), 7.00 (dt, J = 9.0, 2.0 Hz, 2H), 4.08 (t, J = 4.4
Hz, 2H), 4.00 (d, J = 4.4 Hz, 2H), 3.89 (s, 3H), 3.82 (t, J = 5.1 Hz,
4H); J-MOD 13C NMR (100 MHz, CDCl3) δ 170.0, 169.2, 163.6,
163.5, 156.4, 141.9, 139.9, 130.5 (2C), 127.2, 123.7, 121.1, 114.1 (2C),
66.6 (2C), 55.5, 44.0, 43.9; IR (film, cm−1) 3432, 2972, 2932, 2874,
1594, 1573, 1561, 1496, 1447, 1424, 1409, 1373, 1308, 1268, 1259,
1222, 1170, 1140, 1119, 1053, 1030, 1002, 973, 871, 862, 855, 844,
812, 770, 706, 657, 637, 595, 579, 544, 512; MS ESI+ m/z 366.1566
[C19H20N5O3 (M + 1) requires 366.1561]; mp 211−213 °C.
1
general procedure D. H NMR (400 MHz, DMSO-d6) δ 10.73 (br s,
5-Bromo-4-(4-(4-fluorophenyl)-6-phenyl-1,3,5-triazin-2-yl)-
pyridin-3-ol (6b). The title compound was obtained in 75% yield
(0.099 g) as a yellow powder from 5-bromo-2-(4-fluorophenyl)-4H-
pyrido[4,3-e][1,3]oxazin-4-one (2b) (100 mg) according to general
procedure C and 87% yield (0.122 g) as a yellow powder from 2a (100
mg) in the presence of 4b (60 mg, 0.35 mmol) and potassium
1H), 8.38 (dt, J = 7.2, 1.3 Hz, 2H), 8.32 (s, 1H), 8.30 (s, 1H), 7.62 (t, J
= 7.3 Hz, 1H), 7.53 (t, J = 7.3 Hz, 2H), 4.02 (br s, 2H), 3.81 (br s,
2H), 3.75 (br s, 2H), 3.68 (br s, 2H); J-MOD 13C NMR (100 MHz,
DMSO-d6) δ 170.8, 170.7, 164.3, 152.3, 142.0, 138.2, 135.8, 133.2,
132.9, 129.1 (2C), 128.7 (2C), 118.9, 66.2 (2C), 43.9, 43.8; IR (film,
cm−1) 3429, 2969, 2918, 2857, 1594, 1562, 1493, 1466, 1447, 1409,
1386, 1358, 1307, 1268, 1232, 1211, 1179, 1159, 1115, 1069, 1052,
1025, 1008, 973, 895, 865, 834, 824, 786, 764, 706, 696, 678, 653, 573,
548, 511; MS ESI+ m/z 414.0552 [C18H17BrN5O2 (M + 1) requires
414.0560]; mp 169−170 °C.
5-Bromo-4-(4-(3-methoxyphenyl)-6-phenyl-1,3,5-triazin-2-yl)-
pyridin-3-ol (6g). The title compound was obtained in 78% yield
(0.102 g) as a yellow powder from 5-bromo-2-(3-methoxyphenyl)-4H-
pyrido[4,3-e][1,3]oxazin-4-one (2e) (100 mg) according to general
procedure C. 1H NMR (400 MHz, DMSO-d6) δ 10.90 (br s, 1H), 8.61
(dt, J = 7.2, 1.2 Hz, 2H), 8.38 (d, J = 7.0 Hz, 2H), 8.20 (d, J = 7.8 Hz,
1H), 8.09 (t, J = 2.2 Hz, 1H), 7.73 (t, J = 7.3 Hz, 1H), 7.64 (t, J = 7.7
Hz, 2H), 7.56 (t, J = 7.9 Hz, 1H), 7.30 (dd, J = 8.0, 2.1 Hz, 1H), 3.89
(s, 3H); J-MOD 13C NMR (100 MHz, CDCl3) δ 171.4 (2C), 170.4,
160.6, 157.0, 145.6, 141.3, 136.3, 134.9, 134.2, 130.5, 129.7 (2C),
129.5 (2C), 123.6, 122.2, 120.4, 119.5, 114.4, 55.9; IR (film, cm−1)
3428, 3065, 2925, 2853, 1601, 1587, 1546, 1506, 1468, 1448, 1425,
1398, 1350, 1303, 1284, 1254, 1212, 1194, 1176, 1155, 1127, 1080,
1056, 1030, 1005, 994, 918, 894, 871, 839, 788, 756, 714, 689, 677,
1
carbonate (48 mg, 0.35 mmol) according to general procedure D. H
NMR (400 MHz, DMSO-d6) δ 10.80 (br s, 1H), 8.68 (ddt, J = 9.0,
5.6, 2.0 Hz, 2H), 8.61 (dt, J = 7.1, 1.4 Hz, 2H), 8.41 (s, 1H), 8.39 (s,
1H), 7.73 (tt, J = 7.3, 1.3 Hz, 1H), 7.64 (t, J = 7.7 Hz, 2H), 7.46 (tt, J
= 8.8, 2.0 Hz, 2H); J-MOD 13C NMR (100 MHz, DMSO-d6) δ 172.0,
171.8, 170.8, 165.9 (d, J = 251 Hz, 1C), 152.2, 142.1, 138.4, 134.9,
133.9, 132.7, 132.0 (d, J = 9.4 Hz, 2C), 131.5 (d, J = 2.8 Hz, 1C),
129.5 (2C), 129.2 (2C), 118.9, 116.6 (d, J = 21.9 Hz, 2C); 19F NMR
(188 MHz, DMSO-d6) δ −105.9; IR (film, cm−1) 3427, 3063, 2924,
2852, 1600, 1587, 1541, 1503, 1467, 1448, 1418, 1402, 1389, 1350,
1328, 1304, 1238, 1194, 1151, 1134, 1102, 1068, 1052, 1027, 1003,
896, 857, 834, 788, 763, 745, 727, 693, 678, 658, 653, 617, 593, 587,
564, 518; MS ESI+ m/z 423.0243 [C20H13BrFN4O (M + 1) requires
423.0251]; mp 201−203 °C.
5-Bromo-4-(4-(1-methyl-1H-pyrrol-2-yl)-6-phenyl-1,3,5-triazin-2-
yl)pyridin-3-ol (6c). The title compound was obtained in 67% yield
(0.089 g) as a white powder from 5-bromo-2-(1-methyl-1H-pyrrol-2-
yl)-4H-pyrido[4,3-e][1,3]oxazin-4-one (2c) (100 mg) according to
1
general procedure C. H NMR (400 MHz, DMSO-d6) δ 10.78 (br s,
G
dx.doi.org/10.1021/jo5010668 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
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660, 647, 616, 572, 502; MS ESI+ m/z 435.0456 [C21H16BrN4O2 (M
+ 1) requires 435.0451]; mp 147−149 °C.
pyrido[4,3-e][1,3]oxazin-4-one (2g) (0.106 g) according to general
procedure C in 3 mL of EtOH. 1H NMR (400 MHz, CDCl3) δ 12.96
(br s, 1H), 9.12 (s, 1H), 8.64 (d, J = 6.9 Hz, 2H), 8.57 (dd, J = 8.7, 1.7
Hz, 1H), 8.52 (s, 1H), 8.46 (s, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.94 (d, J
= 8.7 Hz, 1H), 7.87 (d, J = 7.6 Hz, 1H), 7.55−7.66 (m, 5H); J-MOD
13C NMR (100 MHz, CDCl3) δ 170.9, 170.8, 169.8, 156.6, 145.1,
140.9, 136.0, 134.4, 133.7, 132.8, 131.6, 131.0, 129.6, 129.3 (2C),
129.0 (2C), 128.8, 128.6, 127.8, 126.8, 124.6, 123.0, 119.0; IR (neat,
cm−1) 3054, 2690, 2873, 1537, 1495, 1461, 1390, 1151, 1115, 952,
837; 784, 756, 469; MS ESI+ m/z 455.0501 [C24H16BrN4O (M + H)
requires 455.0502]; mp 195−197 °C.
5-Bromo-4-(4-(4-methoxyphenyl)-6-morpholino-1,3,5-triazin-2-
yl)pyridin-3-ol (6h). The title compound was obtained in 64% yield
(0.085 g) as a yellow powder from 2d (100 mg) in the presence of 4c
(66 mg, 0.31 mmol) and potassium carbonate (41 mg, 0.30 mmol)
1
according to general procedure D. H NMR (400 MHz, CDCl3) δ
13.81 (br s, 1H), 8.40 (br s, 1H), 8.37 (br s, 1H), 8.30 (dt, J = 8.9, 2.0
Hz, 2H), 6.99 (dt, J = 9.0, 1.9 Hz, 2H), 4.08 (t, J = 4.7 Hz, 4H), 3.89
(s, 3H), 3.81 (q, J = 4.4 Hz, 4H); J-MOD 13C NMR (100 MHz,
CDCl3) δ 169.3, 169.2, 164.1, 163.7, 157.7, 144.7, 140.9, 130.9 (2C),
127.4, 123.9, 119.2, 114.6 (2C), 67.2, 67.1, 55.9, 45.0, 44.4; IR (film,
cm−1) 3424, 3007, 2972, 2919, 2867, 2840, 1593, 1556, 1495, 1466,
1448, 1418, 1365, 1305, 1269, 1236, 1212, 1182, 1171, 1156, 1117,
1073, 1052, 1027, 1009, 973, 891, 857, 850, 818, 785, 770, 691, 638,
597, 570, 549, 518; MS ESI+ m/z 444.0653 [C19H19BrN5O3 (M + 1)
requires 444.0665]; mp 181−183 °C.
4-(4-Amino-6-phenyl-1,3,5-triazin-2-yl)-5-bromopyridin-3-ol
(6k). The title compound was obtained in 93% yield (0.106 g) as a
yellow powder from 2a (100 mg) in the presence of guanidine
hydrochloride (4d) (33 mg, 0.35 mmol) and potassium carbonate (48
1
mg, 0.35 mmol) according to general procedure D. H NMR (400
MHz, DMSO-d6) δ 10.76 (s, 1H), 8.33 (br s, 2H), 8.33 (br s, 2H),
7.85 (br s, 2H), 7.60 (t, J = 7.2 Hz, 1H), 7.52 (t, J = 7.6 Hz, 2H); J-
MOD 13C NMR (100 MHz, DMSO-d6) δ 171.1, 171.0, 167.3, 152.3,
141.9, 138.0, 136.1, 133.3, 132.6, 129.0 (2C), 128.5 (2C), 118.9; IR
(film, cm−1) 3383, 3332, 3138, 3074, 2732, 1675, 1640, 1558, 1517,
1492, 1457, 1412, 1393, 1312, 1217, 1169, 1147, 1110, 1069, 1029,
1005, 968, 900, 868, 847, 825, 788, 766, 709, 685, 660, 622, 603, 570,
513; MS ESI+ m/z 344.0142 [C14H11BrN5O (M + 1) requires
344.0141]; mp 311−313 °C.
4-(4-Amino-6-(4-chlorophenyl)-1,3,5-triazin-2-yl)-5-bromopyri-
din-3-ol (6l). The title compound was obtained in 64% yield (0.073 g)
as a white powder from 2f (0.100 g) in the presence of 4d (1 equiv)
and potassium carbonate (1 equiv) according to general procedure D
in 3 mL of EtOH. 1H NMR (400 MHz, DMSO-d6) δ 10.74 (br s, 1H),
8.32 (d, J = 8.7 Hz, 2H), 8.30 (s, 1H), 8.28 (s, 1H), 7.92 (br s, 2H),
7.61 (d, J = 8.7 Hz, 2H); J-MOD 13C NMR (100 MHz, DMSO-d6) δ
175.9, 175.0, 172.1, 157.0, 146.7, 142.8, 142.3, 139.7, 138.0, 135.0
(2C), 134.0 (2C), 123.6; IR (neat, cm−1) 3371, 3092, 1675, 1582,
1555, 1519, 1506, 1380, 1308, 1217, 1089, 965, 900, 867, 698; MS ESI
+ m/z 377.9750 [C14H10BrClN5O (M + H) requires 377.9751]; mp
306−308 °C.
Sodium (2-Chloronicotinoyl)(4-methoxybenzoyl)amide (10b).
The crude title compound was obtained in 100% yield (2 g) as a
white powder from commercial 2-chloronicotinamide (1 g, 6.39
mmol) in THF (120 mL) according to general procedure E. 1H NMR
(400 MHz, DMSO-d6) δ 8.27 (dd, J = 4.7, 2.0 Hz, 1H), 8.02 (dt, J =
8.9, 2.0 Hz, 2H), 7.87 (dd, J = 7.5, 2.0 Hz, 1H), 7.35 (dd, J = 7.5, 4.7
Hz, 1H), 6.87 (dt, J = 8.9, 2.0 Hz, 2H), 3.78 (s, 3H); J-MOD 13C
NMR (100 MHz, DMSO-d6) δ 174.6, 173.4, 161.3, 148.0, 147.0,
139.1, 138.2, 132.9, 131.0 (2C), 112.9, 113.0 (2C), 55.5; IR (film,
cm−1) 3418, 3073, 3002, 2934, 2837, 1734, 1602, 1574, 1511, 1496,
1448, 1394, 1318, 1303, 1253, 1181, 1159, 1105, 1060, 1030, 905, 848,
826, 781, 761, 714, 693, 649, 634, 603, 572; MS (only the free-imide
NH can be detected) ESI+ m/z 291.0529 [C14H12ClN2O3 (M − Na +
2) requires 291.0531]; mp 287−289 °C.
2-(4-Methoxyphenyl)-4H-pyrido[3,2-e][1,3]oxazin-4-one (3b).
The title compound was obtained in 87% yield (213 mg) as a white
solid from crude sodium (2-chloronicotinoyl)(4-methoxybenzoyl)-
amide (10b) (300 mg, 0.96 mmol) according to general procedure F
in 20 mL of anhydrous acetonitrile at 150 °C with 15 min of MW
irradiation in very high absorption mode. 1H NMR (400 MHz,
DMSO-d6) δ 8.79 (dd, J = 4.8, 2.0 Hz, 1H), 8.48 (dd, J = 7.6, 2.0 Hz,
1H), 8.28 (dt, J = 9.0, 2.0 Hz, 2H), 7.67 (dd, J = 7.7, 4.7 Hz, 1H), 7.20
(dt, J = 9.0, 2.0 Hz, 2H), 3.91 (s, 3H); J-MOD 13C NMR (100 MHz,
CDCl3) δ 167.7, 165.5, 165.0, 160.3, 154.6, 138.5, 132.6 (2C), 124.1,
121.5, 114.9 (2C), 114.0, 56.1; IR (CH2Cl2, cm−1) 3059, 3016, 2975,
2935, 2843, 1692, 1653, 1615, 1608, 1594, 1555, 1512, 1472, 1443,
1425, 1340, 1307, 1283, 1236, 1206, 1171, 1143, 1119, 1101, 1032,
880, 846, 788, 651, 634, 575, 535, 514; MS ESI+ m/z 255.0763
[C14H11N2O3 (M + 1) requires 255.0764]; mp 201−203 °C.
3-(4-(4-Methoxyphenyl)-6-phenyl-1,3,5-triazin-2-yl)pyridin-
2(1H)-one (7b). The title compound was obtained in 82% yield (0.115
g) as a yellow powder from 2-(4-methoxyphenyl)-4H-pyrido[3,2-
e][1,3]oxazin-4-one (3b) (100 mg) according to general procedure C.
General Procedure E: Sodium (3,5-Dibromoisonicotinoyl)(4-
chlorobenzoyl)amide (9f). At 0 °C under an argon atmosphere, to a
solution of commercial 3,5-dibromoisonicotinamide (0.486 g, 1.74
mmol) in THF (50 mL) was added NaH (60% dispersion in oil, 139
mg, 3.47 mmol), and the reaction mixture was then stirred at 0 °C for
1 h. Next, at −78 °C, pure 4-chlorobenzoyl chloride (303 mg, 1.74
mmol) was added, and the reaction mixture was slowly warmed to
room temperature. After one night, the mixture was filtered and
concentrated in vacuo, and the resulting residue was triturated in Et2O
to provide, after filtration, 750 mg (98% yield) of the crude desired
1
compound as a yellow powder. H NMR (400 MHz, DMSO-d6) δ
8.57 (s, 2H), 8.02 (d, J = 8.4 Hz, 2H), 7.40 (d, J = 8.4 Hz, 2H); J-
MOD 13C NMR (100 MHz, DMSO-d6) δ 173.0, 171.8, 153.1, 149.3
(2C), 138.0, 135.1, 130.6 (2C), 127.5 (2C), 116.9 (2C); IR (neat,
cm−1) 2924, 1622, 1589, 1569, 1543, 1403, 1275, 1089, 1012, 897,
758; MS (only the free-imide NH can be detected) ESI+ m/z
416.8633 [C13H8Br2ClN2O2 (M − Na + 2) requires 416.8635]; mp
267−269 °C.
General Procedure F: 5-Bromo-2-(4-chlorophenyl)-4H-
pyrido[4,3-e][1,3]oxazin-4-one (2f). In each of two 10−20 mL
microwave vials was placed 500 mg of crude sodium (3,5-
dibromoisonicotinoyl)(4-chlorobenzoyl)amide (9f). Then 20 mL of
anhydrous DMSO was added to each vial, and the vials were sealed.
The resulting mixtures were then submitted to microwave irradiation
under stirring for 20 min at 180 °C using a Biotage Initiator 2.0
apparatus (in very high absorption mode). After 20 min, the reaction
mixtures were gathered, diluted with 150 mL of AcOEt, and washed
with brine (3 × 150 mL). The organic layer was then dried over
sodium sulfate, filtered, and concentrated in vacuo. The resulting
residue was triturated in Et2O, filtered, and dried under vacuum for 2 h
at 80 °C to yield to 562 mg (74% yield) of the corresponding final
compound as a pale-yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.90
(2s, 2H), 8.35 (ddd, J = 8.8, 4.4, 2.4 Hz, 2H), 7.58 (ddd, J = 8.4, 4.4,
2.8 Hz, 2H); J-MOD 13C NMR (100 MHz, CDCl3) δ 162.5, 161.8,
151.2, 150.8, 141.7, 139.3, 130.8 (2C), 129.4 (2C), 127.0, 121.9,
118.0; IR (neat, cm−1) 3044, 1693, 1592, 1566, 1321, 1241, 1091, 931,
846, 739, 695, 609; MS ESI+ m/z 336.9375 [C13H7BrClN2O2 (M +
H) requires 336.9373]; mp 217−219 °C.
5-Bromo-4-(4-(4-chlorophenyl)-6-phenyl-1,3,5-triazin-2-yl)-
pyridin-3-ol (6i). The title compound was obtained in 69% yield
(0.091 g) as a white powder from 5-bromo-2-(4-chlorophenyl)-4H-
pyrido[4,3-e][1,3]oxazin-4-one (2f) (0.101 g) according to general
procedure C in 3 mL of EtOH. 1H NMR (400 MHz, CDCl3) δ 12.66
(br s, 1H), 8.47−8.50 (m, 4H), 8.43 (s, 1H), 8.36 (s, 1H), 7.57 (m,
1H), 7.43−7.51 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 170.8,
170.2, 169.9, 156.6, 144.8, 140.7, 140.3, 134.0, 133.9, 132.9, 130.6
(2C), 129.3 (2C), 129.2 (2C), 129.0 (2C), 123.1, 119.1; IR (neat,
cm−1) 3069, 1675, 1589, 1538, 1422, 1340, 1285, 921, 845, 795, 739,
700, 609, 482; MS ESI+ m/z 438.9951 [C20H13BrClN4O (M + H)
requires 438.9955]; mp 201−203 °C.
5-Bromo-4-(4-naphthalen-2-yl-6-phenyl-1,3,5-triazin-2-yl)-
pyridin-3-ol (6j). The title compound was obtained in 55% yield
(0.075 g) as a white powder from 5-bromo-2-(naphthalen-2-yl)-4H-
H
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1H NMR (500 MHz, DMSO-d6) δ 12.19 (br s, 1H), 8.63 (d, J = 7.1
137.9, 137.2, 135.0, 133.5, 129.9, 124.5, 113.9; IR (film, cm−1) 3055,
2984, 1734, 1695, 1614, 1588, 1563, 1513, 1470, 1415, 1367, 1338,
1240, 1226, 1205, 1142, 1130, 1099, 1059, 1049, 1011, 896, 869, 859,
787, 618, 534; MS ESI+ m/z 231.0225 [C11H7N2O2S (M + 1) requires
231.0223]; mp 180−182 °C.
Hz, 2H), 8.61 (dt, J = 9.0, 2.0 Hz, 2H), 8.54 (br s, 1H), 7.78 (br s,
1H), 7.69 (tt, J = 7.2, 2.3 Hz, 1H), 7.63 (t, J = 7.7 Hz, 2H), 7.17 (dt, J
= 8.9, 2.8 Hz, 2H), 6.51 (br s, 1H), 3.90 (s, 3H); J-MOD 13C NMR
(100 MHz, CDCl3) δ 170.5, 170.2, 170.0, 165.7, 164.1, 153.1, 139.6,
134.9, 133.2, 131.1 (2C), 129.0 (2C), 128.9 (2C), 127.1, 116.2, 114.3
(2C), 113.8, 55.5; IR (film, cm−1) 3426, 3070, 2935, 2836, 1657, 1608,
1590, 1559, 1535, 1511, 1485, 1449, 1412, 1370, 1347, 1308, 1265,
1238, 1173, 1145, 1104, 1067, 1041, 1030, 994, 897, 888, 833, 805,
775, 695, 644, 592, 510; MS ESI+ m/z 357.1345 [C21H17N4O2 (M +
1) requires 357.1346]; mp 194−195 °C.
3-(4-(4-Fluorophenyl)-6-phenyl-1,3,5-triazin-2-yl)pyridin-2(1H)-
one (7c). The title compound was obtained in 72% yield (0.102 g) as a
white powder from 2-(4-fluorophenyl)-4H-pyrido[3,2-e][1,3]oxazin-4-
one (3c) (100 mg) according to general procedure C and 73% yield
(112 mg) as a white powder from 3a (100 mg) in the presence of 4b
(82 mg, 0.47 mmol) and potassium carbonate (62 mg, 0.45 mmol)
according to general procedure D. 1H NMR (400 MHz, DMSO-d6) δ
12.07 (br s, 1H), 8.71 (ddt, J = 8.9, 5.7, 2.1 Hz, 2H), 8.65 (dt, J = 7.0,
1.5 Hz, 2H), 8.57 (d, J = 6.0 Hz, 1H), 7.77 (br s, 1H), 7.70 (tt, J = 7.2,
1.4 Hz, 1H), 7.63 (tt, J = 7.0, 1.6 Hz, 2H), 7.46 (tt, J = 8.8, 2.0 Hz,
2H), 6.49 (br s, 1H); J-MOD 13C NMR (100 MHz, CDCl3) δ 171.2,
171.1, 170.7, 170.4, 166.7 (d, J = 253 Hz, 1C), 165.9, 153.2, 140.3,
135.0, 134.0, 132.0 (d, J = 9.4 Hz, 2C), 131.4 (d, J = 3.0 Hz, 1C),
129.5 (2C), 129.4 (2C), 116.5 (d, J = 21.9 Hz, 2C), 116.4; 19F NMR
(188 MHz, CDCl3) δ −107.1; IR (film, cm−1) 3429, 3072, 1666, 1603,
1589, 1559, 1511, 1448, 1411, 1366, 1310, 1227, 1176, 1144, 1094,
1059, 1026, 1015, 898, 888, 855, 834, 818, 772, 695, 658, 643, 637,
600, 587, 538, 515, 501; MS ESI+ m/z 345.1144 [C20H14FN4O (M +
1) requires 345.1146]; mp 256−258 °C.
3-(4-Phenyl-6-(thiophen-2-yl)-1,3,5-triazin-2-yl)pyridin-2(1H)-one
(7e). The title compound was obtained in 67% yield (0.097 g) as a
white powder from 2-(thiophen-2-yl)-4H-pyrido[3,2-e][1,3]oxazin-4-
1
one (3e) (100 mg) according to general procedure C. H NMR (400
MHz, CDCl3) δ 13.61 (br s, 1H), 8.98 (dd, J = 7.7, 2.0 Hz, 1H), 8.57
(dt, J = 7.1, 1.8 Hz, 2H), 8.43 (br s, 1H), 8.31 (dd, J = 3.8, 1.2 Hz,
1H), 7.70 (dd, J = 5.0, 1.2 Hz, 1H), 7.64 (tt, J = 7.3, 1.4 Hz, 1H), 7.56
(tt, J = 7.1, 1.6 Hz, 2H), 7.25 (dd, J = 4.9, 3.8 Hz, 1H), 7.03 (dd, J =
7.3, 5.0 Hz, 1H); J-MOD 13C NMR (125 MHz, CDCl3) δ 170.9,
170.1, 167.1, 165.6, 153.0, 140.6, 140.1, 134.5, 133.8, 133.6, 132.8,
129.1 (5C), 116.4, 113.7; IR (film, cm−1) 3428, 3069, 1659, 1589,
1559, 1532, 1511, 1482, 1448, 1437, 1412, 1396, 1372, 1308, 1230,
1175, 1137, 1068, 1048, 1029, 1016, 886, 860, 838, 819, 773, 720, 696,
663, 652, 641, 630, 583, 508; MS ESI+ m/z 333.0809 [C18H13N4OS
(M + 1) requires 333.0804]; mp 235−237 °C.
3-(4-(4-Fluorophenyl)-6-(4-methoxyphenyl)-1,3,5-triazin-2-yl)-
pyridin-2(1H)-one (7f). The title compound was obtained in 80% yield
(0.118 g) as a yellow powder from 3b (100 mg) in the presence of 4b
(72 mg, 0.41 mmol) and potassium carbonate (57 mg, 0.41 mmol)
according to general procedure D. 1H NMR (400 MHz, CDCl3) (NH
does not appear) δ 9.03 (dd, J = 7.7, 2.0 Hz, 1H), 8.67 (dd, J = 8.8, 5.4
Hz, 2H), 8.59 (d, J = 8.9 Hz, 2H), 8.47 (dd, J = 2.8, 2.0 Hz, 1H), 7.27
(tt, J = 8.6, 1.9 Hz, 2H), 7.08 (m, 3H), 3.96 (s, 3H); J-MOD 13C NMR
(100 MHz, CDCl3) δ 170.1, 170.0, 169.6, 166.2 (d, J = 253 Hz, 1C),
165.6, 164.2, 153.0, 139.7, 131.4 (d, J = 7.8 Hz, 2C), 131.2, 131.1
(2C), 126.9, 116.1, 116.0 (d, J = 23.3 Hz, 2C), 114.4 (2C), 113.8,
55.5; 19F NMR (188 MHz, CDCl3) δ −105.4; IR (film, cm−1) 3436,
3075, 3006, 2933, 2837, 1666, 1601, 1587, 1533, 1508, 1411, 1370,
1348, 1306, 1257, 1227, 1173, 1145, 1103, 1029, 888, 859, 828, 799,
772, 730, 689, 656, 637, 592, 588, 511; MS ESI+ m/z 375.1258
[C21H16FN4O2 (M + 1) requires 375.1251]; mp 191−192 °C.
3-(4-Amino-6-phenyl-1,3,5-triazin-2-yl)pyridin-2(1H)-one (7g).
The title compound was obtained in 97% yield (0.172 g) as a yellow
powder from 3a (150 mg) in the presence of 4d (67 mg, 0.70 mmol)
and potassium carbonate (92 mg, 0.67 mmol) according to general
procedure D. 1H NMR (400 MHz, DMSO-d6) (NH does not appear)
δ 8.39 (d, J = 7.0 Hz, 2H), 8.30 (d, J = 6.0 Hz, 1H), 7.97 (d, J = 2.9
Hz, 1H), 7.57 (m, 3H), 6.50 (t, J = 5.7 Hz, 1H); J-MOD 13C NMR
(100 MHz, DMSO-d6) δ 170.9, 170.5, 166.5, 164.3, 148.3, 140.3,
136.3, 132.5, 129.0 (2C), 128.5 (2C), 118.8, 111.9; IR (film, cm−1)
3346, 3209, 1661, 1638, 1602, 1561, 1521, 1466, 1436, 1384, 1312,
1301, 1235, 1159, 1135, 1084, 1058, 1030, 996, 898, 878, 832, 812,
781, 767, 720, 698, 668, 635, 623, 601, 582, 536, 516; MS ESI+ m/z
266.1031 [C14H12N5O (M + 1) requires 266.1036]; mp >315 °C.
3-(4-(4-Fluorophenyl)-6-morpholino-1,3,5-triazin-2-yl)pyridin-
2(1H)-one (7h). The title compound was obtained in 61% yield (0.089
g) as a white powder from 3c (100 mg) in the presence of 4c (91 mg,
0.43 mmol) and potassium carbonate (57 mg, 0.41 mmol) according
3-(4-(1-Methyl-1H-pyrrol-2-yl)-6-phenyl-1,3,5-triazin-2-yl)pyridin-
2(1H)-one (7d). The title compound was obtained in 86% yield (0.125
g) as a white powder from 2-(1-methyl-1H-pyrrol-2-yl)-4H-pyrido-
[3,2-e][1,3]oxazin-4-one (3d) (100 mg) according to general
1
procedure C. H NMR (500 MHz, CDCl3) δ 13.95 (br s, 1H), 8.91
(dd, J = 7.6, 1.9 Hz, 1H), 8.50 (dt, J = 7.3, 1.2 Hz, 2H), 8.41 (br d, J =
2.1 Hz, 1H), 7.61 (tt, J = 7.3, 1.2 Hz, 1H), 7.54 (m, 3H), 7.01 (dd, J =
7.6, 4.8 Hz, 1H), 6.96 (t, J = 2.0 Hz, 1H), 6.29 (dd, J = 4.1, 2.4 Hz,
1H), 4.27 (s, 3H); J-MOD 13C NMR (100 MHz, CDCl3) δ 170.0,
169.6 (2C), 165.8, 164.8, 139.3 (2C), 135.2, 133.0, 132.3, 128.9 (2C),
128.8 (2C), 128.4, 120.1, 116.3, 109.6, 38.9; IR (film, cm−1) 3428,
3110, 3067, 3002, 2955, 1660, 1591, 1536, 1516, 1477, 1438, 1396,
1373, 1343, 1309, 1271, 1254, 1227, 1177, 1144, 1108, 1093, 1069,
1058, 1027, 1010, 992, 887, 829, 844, 801, 776, 738, 695, 659, 650,
642, 634, 604, 578, 517; MS ESI+ m/z 330.1348 [C19H16N5O (M + 1)
requires 330.1349]; mp 197−199 °C.
Sodium (2-Chloronicotinoyl)(thiophene-2-carbonyl)amide (10e).
The title compound was obtained in 97% yield (0.896 g) as a yellow
powder from commercial 2-chloronicotinamide (500 mg, 3.19 mmol)
and commercial thiophene-2-carbonyl chloride (515 mg, 3.51 mmol)
1
according to general procedure E. H NMR (500 MHz, DMSO-d6) δ
8.29 (dd, J = 4.7, 2.0 Hz, 1H), 7.86 (dd, J = 7.5, 2.0 Hz, 1H), 7.52
(ddd, J = 5.4, 3.8, 1.1 Hz, 2H), 7.36 (dd, J = 7.5, 4.7 Hz, 1H), 7.02 (dd,
J = 5.0, 3.7 Hz, 1H); J-MOD 13C NMR (125 MHz, DMSO-d6) δ
173.3, 169.7, 147.9, 146.8, 146.7, 138.3, 137.8, 129.6, 128.9, 127.2,
122.5; IR (film, cm−1) 3432, 3075, 2926, 1734, 1605, 1575, 1555,
1501, 1417, 1398, 1361, 1290, 1251, 1221, 1118, 1097, 1076, 1059,
1042, 1021, 985, 915, 860, 828, 801, 779, 757, 712, 707, 650, 629, 609,
550; MS (only the free-imide NH can be detected) ESI+ m/z
266.9984 [C11H8ClN2O2S (M − Na + 2) requires 266.9989]; mp
190−192 °C.
1
to general procedure D. H NMR (400 MHz, CDCl3) δ 14.1 (br s,
1H), 8.75 (dd, J = 7.6, 2.0 Hz, 1H), 8.38 (m, 3H), 7.18 (tt, J = 9.6, 2.1
Hz, 2H), 6.95 (dd, J = 7.7, 4.8 Hz, 1H), 4.07 (br s, 2H), 3.99 (br s,
2H), 3.82 (t, J = 5.1 Hz, 4H); J-MOD 13C NMR (100 MHz, CDCl3) δ
170.0, 169.0, 166.2 (d, J = 252 Hz, 1C), 166.1, 163.8, 153.2, 139.5,
131.6 (d, J = 2.1 Hz, 1C), 131.3 (d, J = 9.1 Hz, 2C), 116.3, 116.2 (d, J
= 21.7 Hz, 2C), 114.1, 67.1, 67.0, 44.4, 44.3; 19F NMR (188 MHz,
CDCl3) δ −108.2; IR (film, cm−1) 3432, 3070, 2962, 2861, 1659,
1606, 1590, 1561, 1503, 1485, 1447, 1425, 1407, 1379, 1370, 1305,
1275, 1235, 1202, 1147, 1117, 1071, 1042, 1001, 973, 886, 849, 822,
795, 772, 745, 715, 678, 660, 633, 616, 588, 545, 516, 504; MS ESI+
m/z 354.1365 [C18H17FN5O2 (M + 1) requires 354.1360]; mp 228−
230 °C.
2-(Thiophen-2-yl)-4H-pyrido[3,2-e][1,3]oxazin-4-one (3e). The
title compound was obtained in 71% yield (0.169 g) as a white
powder from sodium (2-chloronicotinoyl)(thiophene-2-carbonyl)-
amide (10e) (300 mg) according to general procedure F in 20 mL
of anhydrous acetonitrile at 150 °C with 15 min of MW irradiation in
1
very high absorption mode. H NMR (400 MHz, DMSO-d6) δ 8.78
3-(4-(4-Methoxyphenyl)-6-morpholino-1,3,5-triazin-2-yl)pyridin-
2(1H)-one (7i). The title compound was obtained in 88% yield (0.127
g) as a white powder from 3b (100 mg) in the presence of 4c (87 mg,
0.41 mmol) and potassium carbonate (57 mg, 0.41 mmol) according
(dd, J = 4.7, 2.0 Hz, 1H), 8.46 (dd, J = 7.7, 2.0 Hz, 1H), 8.18 (d, J =
4.4 Hz, 2H), 7.67 (dd, J = 7.6, 4.7 Hz, 1H), 7.38 (t, J = 4.4 Hz, 1H); J-
MOD 13C NMR (100 MHz, DMSO-d6) δ 166.8, 160.5, 159.6, 154.6,
I
dx.doi.org/10.1021/jo5010668 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1
to general procedure D. H NMR (400 MHz, CDCl3) δ 14.5 (br s,
combined organic layers were dried over Na2SO4, filtered, and
concentrated in vacuo. The resulting residue was purified on silica gel
to provide 117 mg (74% yield) of the desired product 5i as a pale-
yellow powder.
Similarly, 6h and 7h were obtained in 56% yield (125 mg) and 55%
yield (98 mg) from sodium (3,5-dibromoisonicotinoyl)(4-
methoxybenzoy)amide (9d) (218 mg) and sodium (2-
chloronicotinoyl)(4-fluorobenzoyl)amide (10c) (150 mg) respec-
tively, according to general procedure H.
Compounds 7a, 7b, and 7c were obtained in 84% (195 mg), 75%
(171 mg) and 48% (109 mg) from sodium benzoyl(2-
chloronicotinoyl)amide (10a) (200 mg), 10b (200 mg), and 10c
(200 mg), respectively, according to general procedure G, but the
MW-assisted reactions were performed in acetonitrile at 150 °C for 20
min.
Multigram-Scale Procedure: “One-Pot Process” for the
Preparation of 3-(4,6-Diphenyl-1,3,5-triazin-2-yl)pyridin-
2(1H)-one (7a). Compound 10a (2 g, 7.08 mmol) was equally
distributed into four MW vials (4 × 500 mg) and then diluted with 20
mL of acetonitrile in each vial. Benzamidine 4a (213 g, 1.77 mmol)
was added to each of the four reaction mixtures, and then the
microwave vials were sealed and submitted to microwave irradiation
for 20 min at 150 °C using a Biotage Initiator 2.0 apparatus (in very
high absorption mode). Then the reaction mixtures were gathered,
diluted with CH2Cl2, and concentrated in vacuo. The resulting residue
was purified on silica gel to provide 1.345 g (58% yield) of the desired
product 7a as a white powder.
1H), 8.74 (dd, J = 7.6, 2.0 Hz, 1H), 8.37 (dd, J = 4.8, 2.1 Hz, 1H), 8.33
(d, J = 8.9 Hz, 2H), 7.00 (dt, J = 8.9, 2.7 Hz, 2H), 6.93 (dd, J = 7.6, 4.8
Hz, 1H), 4.07 (br s, 2H), 4.00 (br s, 2H), 3.88 (s, 3H), 3.82 (t, J = 5.1
Hz, 4H); J-MOD 13C NMR (100 MHz, CDCl3) δ 169.3, 168.9, 165.9,
163.5, 163.4, 152.7, 138.9, 130.5 (2C), 127.3, 115.8, 114.1 (2C), 113.7,
66.6 (2C), 55.5, 44.0, 43.9; IR (film, cm−1) 3431, 3066, 3003, 2962,
2917, 2863, 2840, 1660, 1596, 1583, 1557, 1502, 1465, 1455, 1444,
1419, 1383, 1370, 1307, 1273, 1255, 1202, 1187, 1173, 1152, 1142,
1112, 1071, 1043, 1022, 1002, 972, 927, 885, 861, 848, 821, 797, 777,
749, 714, 685, 662, 648, 634, 616, 595, 546, 517; MS ESI+ m/z
366.1552 [C19H20N5O3 (M + 1) requires 366.1560]; mp 236−238 °C.
Sodium Benzoyl(2-chloronicotinoyl)amide (10a). The crude title
compound was obtained in 95% yield (1.81 g) as a white powder from
commercial 2-chloronicotinamide (1 g, 6.39 mmol) in THF (120 mL)
and commercial benzoyl chloride (0.78 mL, 6.71 mmol) according to
general procedure E. 1H NMR (400 MHz, DMSO-d6) δ 8.26 (dd, J =
4.7, 2.0 Hz, 1H), 8.04 (dt, J = 6.7, 1.3 Hz, 2H), 7.85 (dd, J = 7.5, 2.0
Hz, 1H), 7.31−7.40 (m, 4H); J-MOD 13C NMR (100 MHz, DMSO-
d6) δ 174.6, 173.9, 148.0, 147.0, 140.4, 139.1, 138.2, 130.3, 129.1 (2C),
127.8 (2C), 122.9; IR (film, cm−1) 3422, 3055, 1740, 1613, 1577,
1502, 1486, 1449, 1394, 1315, 1295, 1252, 1165, 1125, 1102, 1061,
1043, 1023, 901, 822, 765, 734, 703, 687, 662, 626, 578; MS (only the
free-imide NH can be detected) ESI+ m/z 261.0418 [C13H10ClN2O2
(M − Na + 2) requires 261.0425]; mp 186−188 °C.
Sodium (2-Chloronicotinoyl)(4-fluorobenzoyl)amide (10c). The
crude title compound was obtained in 100% yield (1.92 g) as a white
powder from commercial 2-chloronicotinamide (1 g, 6.39 mmol) in
THF (120 mL) and commercial 4-fluorobenzoyl chloride (0.79 mL,
Similarly, compound 7b was obtained in 71% yield (1.623 g) as a
yellow powder from 2 g of 10b according to the multigram-scale
procedure.
1
6.71 mmol) according to general procedure E. H NMR (400 MHz,
DMSO-d6) δ 8.28 (dd, J = 4.7, 2.0 Hz, 1H), 8.10 (ddt, J = 8.8, 6.0, 2.0
Hz, 2H), 7.88 (dd, J = 7.5, 2.0 Hz, 1H), 7.35 (dd, J = 7.4, 4.7 Hz, 1H),
7.13 (tt, J = 9.0, 2.1 Hz, 2H); J-MOD 13C NMR (100 MHz, DMSO-
d6) δ 174.0, 173.5, 163.9 (d, J = 245 Hz, 1C), 148.2, 147.0, 138.9,
138.3, 136.9, 131.5 (d, J = 8.7 Hz, 2C), 122.9, 114.5 (d, J = 21.1 Hz,
2C); 19F NMR (188 MHz, CDCl3) δ −111.8; IR (film, cm−1) 3417,
3071, 1622, 1599, 1589, 1558, 1510, 1444, 1387, 1310, 1292, 1226,
1175, 1148, 1099, 1061, 1014, 854, 843, 829, 794, 780, 761, 726, 710,
684, 645, 592, 557; MS (only the free-imide NH can be detected) ESI
+ m/z 279.0332 [C13H9ClFN2O2 (M − Na + 2) requires 279.0331];
mp 278−280 °C.
ASSOCIATED CONTENT
■
S
* Supporting Information
Scope and limitations of the transformation of pyrido-
oxazinones into trisubstituted 1,3,5-triazines (Table S1); one-
pot process for the preparation of 6a from 9a in EtOH
(Scheme S1); copies of 1H and 13C NMR spectra of
compounds 2f, 3b, 3e, 5a−i, 6a−l, 7a−i, 9f, 10a−c, and 10e;
and mass spectra of compounds 6a, 6h, and 6i. This material is
available free of charge via the Internet at http://pubs.acs.org.
General Procedure G: “One-Pot Process” for the Preparation
of 4-(4,6-Diphenyl-1,3,5-triazin-2-yl)pyridin-3-ol (5a). In a 10−
AUTHOR INFORMATION
■
20 mL MW vial, to
a solution of sodium benzoyl(3-
bromoisonicotinoyl)amide (8a) (200 mg, 0.61 mmol) in DMSO (12
mL) was added 4a (73 mg, 0.61 mmol). Then the microwave vial was
sealed and submitted to microwave irradiation for 30 min at 180 °C
using a Biotage Initiator 2.0 apparatus (in very high absorption mode).
After 30 min, the whole mixture was transferred to a separatory funnel
containing 100 mL of an aqueous solution of NaCl and extracted with
CH2Cl2 (2 × 100 mL). Then the combined organic layers were dried
over Na2SO4, filtered, and concentrated in vacuo. The resulting residue
was purified on silica gel to provide 142 mg (71%) of the desired
product 5a as a yellow-brown powder.
Similarly, compounds 5b, 5d, 6a, and 6i were obtained in yields of
47% (94 mg), 75% (150 mg), 45% (89 mg), and 48% (104 mg) from
sodium (3-bromoisonicotinoyl)(4-fluorobenzoyl)amide (8b) (200
mg), sodium (3-bromoisonicotinoyl)(4-methoxybenzoyl)amide (8d)
(200 mg), sodium benzoyl(3,5-dibromoisonicotinoyl)amide (9a) (200
mg), and 9f (220 mg), respectively, according to general procedure G.
General Procedure H: “One-Pot Process” for the Preparation
of 4-(4-(4-Methoxyphenyl)-6-morpholino-1,3,5-triazin-2-yl)-
pyridin-3-ol (5i). In a MW vial, a solution of 4c (96 mg, 0.46
mmol) and potassium carbonate (60 mg, 0.43 mmol) in DMSO (5
mL) was stirred for 15 min, and then 8d (155 mg, 0.43 mmol) was
added. The microwave vial was sealed and submitted to microwave
irradiation for 30 min at 180 °C using a Biotage Initiator 2.0 apparatus
(in very high absorption mode). After 30 min, the whole mixture was
transferred to a separatory funnel containing 10 mL of an aqueous
solution of NaCl and extracted with CH2Cl2 (2 × 10 mL). Then the
Corresponding Authors
*E-mail: franck.slowinski@sanofi.com.
*E-mail: candice.botuha@upmc.fr.
*E-mail: serge.thorimbert@upmc.fr.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the analytical sciences department of Sanofi
R&D, France, and CNRS and UPMC for funding (L.L.F.).
Analytical equipment (UPMC) was generously offered through
FR 2769.
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